The novel compounds according to the present invention differ substantially from known, similarly constructed glycosides in that they contain, in the genin-portion of the molecule, a cyano group or an acylated oxime group. This group of compounds possesses valuable pharmacological properties. Used in appropriate doses, they provide improvement in the contractile power of the heart muscle and are, therefore, suitable in cardiac therapy, particularly for the treatment of cardiac insufficiencies.
Peruvoside is a naturally occurring glycoside which can be obtained, for example, from Apocynacea Thevetia neriifolia. It is well known that this glycoside has only limited usefulness in cardiac therapy because it provides for only moderate enteral resorption.
Another problem associated with peruvoside is the relative ease with which it is metabolized. Thus, when radio-marked peruvoside is injected in test animals, peruvosidic acid is one of the metabolites detected [Arzneim. Forsch. 18, 1605, (1968)]. It is also known that the aldehyde group of cardiac glycosides undergoes reduction in animals to form 19-hydroxy derivatives which are subject to further metabolic activity such as glucuronidation [Arch. Exp. Path. Pharmacol. 247, 71(1964) or Arch. Int. Pharmacodyn. 156, 489 (1965)].
On the other hand, the present peruvoside derivatives successfully overcome the deficiencies of the prior art compounds. More specifically, a significant improvement in enteral resorption is observed because the present compounds provide for etherification or esterification of the hydroxyl groups attached to the sugar portion of the molecule. This results in a reduction of the polarity of the molecule which is directly responsible for the desired increase in enteral resorption. Polarity reduction is also enhanced by the presence of the acylated oxime group.
By etherifying and esterifying the hydroxyl groups with the carboalkoxy, alkoxymethyl, and acyl groups of the present invention, the former groups are afforded protection until after resorption. The latter groups are easily metabolized subsequent to resorption.
Additionally, the acylated oxime compounds as shown in formula I and the tertiary cyano compounds of formula II provide for a reduced amount of cardioactive and cardioinactive metabolites as compared with the aldehyde group-containing peruvoside of the prior art.